Clinical Trials in Uveitis

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Article initiated by:

Amin Nabavi, MD, FICO

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Amin Nabavi, MD, FICO

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Introduction

Clinical trials have been essential in defining evidence-based management of intraocular inflammation, particularly in determining the effectiveness and safety of local and systemic treatment strategies. In uveitis, landmark randomized and controlled studies have clarified the role of corticosteroid implants, systemic immunosuppressive therapy, and targeted biologic agents, while addressing key clinical questions such as inflammation control, relapse prevention, and steroid-sparing treatment. This article highlights selected landmark clinical trials that have shaped current approaches to the management of uveitis and continue to inform ongoing research.

Landmark Clinical Trials in Non-Infectious Uveitis

MUST (Multicenter Uveitis Steroid Treatment) Trial (2011)

Objectives

To compare systemic corticosteroid–based therapy with immunosuppressive agents as needed versus local sustained-release corticosteroid therapy using a 0.59-mg fluocinolone acetonide intravitreal implant for non-infectious intermediate uveitis, posterior uveitis, and panuveitis, focusing on visual outcomes, inflammation control, adverse effects, and quality of life.

Design

A U.S.-based, NIH-funded, investigator-initiated, multicenter, randomized, controlled comparative-effectiveness trial. Patients with non-infectious intermediate/posterior/panuveitis were randomized to either:

1. Implant strategy: surgical placement of the 0.59 mg fluocinolone acetonide intravitreal implant (sustained delivery over approximately 2.5–3 years), with standard management of implant-related ocular side effects; or
2. Systemic strategy: oral corticosteroids with structured tapering and addition of systemic immunosuppressive agents when needed to achieve steroid-sparing control. Participants were followed with standardized assessments of best-corrected visual acuity, inflammatory control, vision-related quality of life, and adverse events, with several published reports providing intermediate and long-term outcomes.

Results

• Visual acuity: At 2 years, both strategies improved vision overall, and the trial did not demonstrate clear superiority of one strategy over the other at that primary time point. With extended follow-up, published analyses reported better long-term visual acuity with systemic therapy (at 7 years, systemic therapy favored by 7 letters on average).
• Inflammation control: Inflammation control generally favored the implant strategy earlier in follow-up. In the 2-year trial report, control of uveitis was more frequent with implant therapy ( 88% vs 71% controlled at 24 months).  In the 54-month report, overall control of inflammation remained superior in the implant group at every assessed time point, although most eyes in the systemic arm also achieved complete control or low levels of inflammation over time.
• Complications: Ocular adverse events were markedly higher with implant therapy over long follow-up. By 7 years, IOP-lowering surgery occurred in 45% of eyes assigned to implant therapy versus 12% assigned to systemic therapy.  Among phakic eyes, 90% in the implant group underwent cataract surgery (mostly in the first 2 years) versus 50% in the systemic group.  

Conclusions

The MUST Trial established that both systemic therapy and the fluocinolone implant strategy can be effective for non-infectious intermediate/posterior/panuveitis. However, the implant strategy is associated with a substantially higher risk of cataract and IOP elevation/glaucoma-related interventions, whereas systemic therapy, when appropriately monitored and used in a steroid-sparing framework, supports strong long-term outcomes and, in long-term follow-up reports, was associated with better visual acuity on average.

HURON Trial (2011)

Objectives

To evaluate the efficacy and safety of a single intravitreal dexamethasone implant compared with sham injection for the treatment of non-infectious intermediate and posterior uveitis, with emphasis on inflammation control, visual outcomes, and treatment-related adverse events.

Design

An industry-sponsored, international, multicenter, randomized, masked, sham-controlled Phase III clinical trial. Patients with non-infectious intermediate or posterior uveitis were randomized to receive a dexamethasone intravitreal implant (0.7 mg or 0.35 mg) or a sham procedure. Participants were followed for 26 weeks, with standardized assessments of vitreous haze, visual acuity, and ocular safety outcomes.

Results

• Inflammation control: At 8 weeks, a significantly higher proportion of eyes treated with the dexamethasone implant achieved a vitreous haze score of 0 compared with sham (47% in the 0.7 mg group, 36% in the 0.35 mg group, vs 12% in the sham group). The anti-inflammatory effect was observed early and was maintained through the study follow-up period.

• Visual acuity: Eyes receiving the dexamethasone implant demonstrated greater improvement in best-corrected visual acuity, including a higher proportion achieving a ≥15-letter gain, compared with sham-treated eyes at key study visits.

• Complications: Ocular adverse events were consistent with known corticosteroid-related effects. IOP elevation occurred more frequently in implant-treated eyes but was generally manageable with medical therapy. Cataract progression was observed during follow-up, particularly in phakic eyes.

Conclusions

The HURON Trial demonstrated that a single dexamethasone intravitreal implant provides rapid and clinically meaningful reduction of intraocular inflammation with associated visual improvement in non-infectious intermediate and posterior uveitis. The study established the dexamethasone implant as an effective local corticosteroid treatment option, particularly when short- to intermediate-term inflammation control is desired, with an expected corticosteroid-related ocular safety profile.

VISUAL I: Adalimumab in Active Non-Infectious Uveitis (2016)

Objectives

To determine whether adalimumab prolongs time to treatment failure compared with placebo in adults with active non-infectious intermediate uveitis, posterior uveitis, or panuveitis requiring systemic corticosteroids. 

Design

An industry-sponsored, international, multicenter, randomized, double-masked, placebo-controlled phase III trial. Patients with active NIU received a standardized prednisone regimen with a predefined taper and were randomized to adalimumab or placebo, with the primary endpoint being time to treatment failure (a composite endpoint based on inflammatory activity and vision-related criteria). 

Results

• Primary outcome: Adalimumab significantly reduced the risk of treatment failure compared with placebo (HR 0.50; 95% CI 0.36–0.70; P<0.001). Median time to treatment failure was 24 weeks with adalimumab versus 13 weeks with placebo.

• Other outcomes: Adalimumab improved multiple components of intraocular inflammation that contributed to treatment failure, including vitreous haze, anterior chamber cell grade, new active inflammatory lesions, and vision loss (≥15-letter BCVA worsening). Secondary analyses also demonstrated better overall control of ocular inflammation and modest improvement in visual acuity (mean difference −0.07) compared with placebo. Differences in macular edema outcomes were not statistically significant in the prespecified hierarchical analysis.
• Complications / adverse events: Adalimumab was associated with higher rates of adverse events and serious adverse events compared with placebo (28.8 vs 13.6 per 100 person-years), consistent with the known safety profile of systemic anti-TNF therapy. Rates of serious infections were similar between groups, and no new or unexpected safety signals were identified.

Conclusions

In active non-infectious intermediate/posterior/panuveitis, adalimumab significantly prolonged time to treatment failure and supported disease control during corticosteroid tapering, establishing anti-TNF therapy as an evidence-based option in appropriately selected patients.

VISUAL II: Adalimumab for Prevention of Flare in Inactive Non-Infectious Uveitis (2016)

Objectives

To evaluate whether adalimumab reduces the risk of uveitic flare / treatment failure compared with placebo in adults with inactive non-infectious intermediate uveitis, posterior uveitis, or panuveitis controlled by systemic corticosteroids, during mandated corticosteroid withdrawal. 

Design

An industry-sponsored, international, multicenter, randomized, double-masked, placebo-controlled phase 3 trial. Patients with inactive NIU entered on systemic corticosteroids and underwent a predefined prednisone taper to discontinuation while receiving adalimumab or placebo. Primary endpoint was time to treatment failure (composite endpoint). 

Results

• Primary outcome: Adalimumab significantly reduced the risk of uveitic flare or treatment failure during corticosteroid withdrawal compared with placebo (HR 0.57; 95% CI 0.39–0.84; P=0.004). Median time to treatment failure was not reached in the adalimumab group and was 8.3 months in the placebo group.
• Other outcomes: Adalimumab was more effective in maintaining disease quiescence, with fewer patients experiencing treatment failure overall (39% with adalimumab vs 55% with placebo). The largest between-group difference was observed for visual acuity–related treatment failure, occurring in 9% of adalimumab-treated patients compared with 21% of placebo-treated patients. Differences in individual inflammatory measures and macular edema outcomes were not statistically significant in the prespecified hierarchical analysis.
• Complications / adverse events: Overall rates of adverse events were similar between treatment groups, and no new safety concerns were identified. Common adverse events included arthralgia, nasopharyngitis, and headache, consistent with prior experience with adalimumab.

Conclusions

In steroid-dependent inactive NIU, adalimumab significantly reduced the risk of treatment failure and helped maintain disease control during corticosteroid withdrawal, supporting its role as a steroid-sparing maintenance therapy in selected patients.  

SYCAMORE Trial (2017)

Objectives

To determine whether adding adalimumab to methotrexate improves control of juvenile idiopathic arthritis (JIA)–associated uveitis that remains active despite methotrexate, and to assess safety. 

Design

An industry-sponsored, international (United Kingdom and Europe), multicenter, randomized, double-masked, placebo-controlled trial in children with active JIA-associated uveitis despite stable methotrexate therapy. Participants continued methotrexate and were randomized (2:1) to adalimumab or placebo, with treatment failure defined by a prespecified composite of uveitis activity criteria; the trial was stopped early after meeting prespecified efficacy stopping criteria. 

Results

• Primary outcome: Adalimumab significantly reduced the risk of treatment failure compared with placebo (HR 0.25; 95% CI 0.12–0.49; P<0.0001). Treatment failure occurred in 27% (16/60) of the adalimumab group versus 60% (18/30) of the placebo group, and median time to treatment failure was not reached in the adalimumab group and 24.1 weeks in the placebo group.
• Other outcomes: Adalimumab delayed time to treatment failure and improved overall uveitis control in methotrexate-refractory JIA-associated uveitis.  A significantly higher proportion of patients receiving adalimumab were able to reduce or discontinue topical glucocorticoids, and no patients in the adalimumab group experienced an arthritis flare during the trial period, compared with 10% in the placebo group.
• Complications / adverse events: Serious adverse events occurred more frequently in the adalimumab group than placebo in the trial report; overall safety findings were consistent with the known systemic anti-TNF profile in pediatric patients. 

Conclusions

The SYCAMORE Trial established that adalimumab plus methotrexate is superior to methotrexate alone for controlling methotrexate-refractory JIA-associated uveitis, significantly reducing treatment failure and supporting its role as a key steroid-sparing therapy in this population.

POINT Trial (2019)

(PeriOcular vs INTravitreal corticosteroids for uveitic macular edema)

Objectives

To compare the effectiveness and safety of three commonly used regional corticosteroid therapies, periocular triamcinolone acetonide, intravitreal triamcinolone acetonide, and the intravitreal dexamethasone implant, for the treatment of uveitic macular edema, with primary assessment based on OCT-measured central subfield thickness (CST). 

Design

A publicly funded, investigator-initiated, multicenter, randomized, comparative clinical trial conducted by the MUST Research Group, enrolling adults with NIU and macular edema. Participants were randomized (1:1:1) to periocular triamcinolone (40 mg), intravitreal triamcinolone (4 mg), or intravitreal dexamethasone implant (0.7 mg). The primary outcome was the proportion of baseline central subfield thickness at 8 weeks, assessed by masked OCT reading centers, with follow-up through 24 weeks. The trial was stopped early after prespecified efficacy criteria were met at interim analysis. 

Results

• Primary outcome: All three treatment groups demonstrated significant improvement in macular edema. At 8 weeks, intravitreal triamcinolone and the dexamethasone implant produced greater reductions in CST compared with periocular triamcinolone (mean reductions of 39% and 46% vs 23%, respectively; P<0.0001). The dexamethasone implant was non-inferior to intravitreal triamcinolone for the primary outcome. 
• Other outcomes: Both intravitreal treatment arms achieved higher rates of ≥20% improvement and resolution of macular edema compared with periocular therapy, particularly during early follow-up. BCVA improved in all groups, with intravitreal therapies providing approximately 5 additional letters of visual gain compared with periocular treatment by 8 weeks. No clinically meaningful differences in visual acuity outcomes were observed between the two intravitreal therapies. 
• Complications / adverse events: The risk of IOP elevation ≥24 mmHg was higher with intravitreal triamcinolone (34%) and dexamethasone implant (32%) than with periocular triamcinolone (12%), without a significant difference between the two intravitreal therapies. Cataract surgery was uncommon during follow-up (≤6% across groups). Severe IOP elevation, glaucoma surgery, hypotony, and vision loss ≥15 letters were uncommon across all groups during the 24-week follow-up. 

Conclusions

The POINT Trial demonstrated that intravitreal corticosteroid therapies are more effective than periocular corticosteroids for the treatment of uveitic macular edema, providing faster and greater anatomic and visual improvement, at the cost of a modestly increased risk of IOP elevation. Intravitreal dexamethasone implant and intravitreal triamcinolone showed comparable efficacy and safety, supporting intravitreal therapy as a preferred regional treatment strategy for uveitic macular edema.

ADJUST Trial (2025)

(Adalimumab in Juvenile Idiopathic Arthritis–Associated Uveitis Stopping Trial)

Objectives

To assess the efficacy and safety of discontinuing adalimumab compared with continuing therapy in patients with JIA–associated uveitis who had achieved sustained corticosteroid-sparing disease control.

Design

A publicly funded, investigator-initiated, randomized, double-masked, placebo-controlled trial conducted at 20 ophthalmology and rheumatology centers across the USA, UK, and Australia. Patients aged ≥2 years with controlled uveitis and arthritis for at least 1 year on stable adalimumab therapy were randomized (1:1) to continue adalimumab or switch to placebo. The primary endpoint was time to treatment failure, defined by recurrence of uveitis, arthritis, or both. The trial was stopped early after prespecified interim efficacy criteria were met.

Results

• Primary outcome: Discontinuation of adalimumab resulted in a markedly higher risk of treatment failure compared with continuation (HR 8.7; 95% CI 3.6–21.2; P<0.0001). Treatment failure occurred in 68% of patients assigned to placebo versus 14% of patients who continued adalimumab. The median time to treatment failure in the placebo group was 119 days, with most recurrences occurring within the first 24 weeks.
• Other outcomes: Treatment failures were most commonly driven by recurrence of ocular inflammation. Visual acuity did not differ significantly between groups over follow-up, likely reflecting close monitoring and prompt reinitiation of therapy after relapse. Among patients who experienced treatment failure, all regained control of inflammation after restarting adalimumab, with a median time to sustained control of approximately 105 days.
• Complications / adverse events: Non-serious adverse events were slightly more frequent in the adalimumab group (7.5 vs 6.8 events per person-year). Adverse events were consistent with the known safety profile of anti–TNF therapy, with higher rates of infection, including COVID-19, observed in the adalimumab group. No unexpected safety signals were identified.

Conclusions

The ADJUST Trial demonstrated that stopping adalimumab in patients with controlled JIA–associated uveitis carries a high risk of disease recurrence, even after prolonged remission. However, disease control was reliably re-established after treatment reinitiation.

Ongoing Clinical Trials

CLARITY Trial (Brepocitinib)

The CLARITY trial is an industry-sponsored, international, multicenter, randomized, double-masked Phase 3 clinical study evaluating brepocitinib, an oral dual TYK2/JAK1 inhibitor, in adults with active non-anterior non-infectious uveitis (intermediate, posterior, or panuveitis). The trial is designed to assess the efficacy of brepocitinib in reducing treatment failure and intraocular inflammation compared with placebo, with additional evaluation of visual outcomes and safety.

MEERKAT and SANDCAT Trials (Vamikibart)

MEERKAT and SANDCAT are industry-sponsored, international, multicenter, randomized, double-masked, sham-controlled Phase 3 trials investigating vamikibart, an intravitreal IL-6 pathway inhibitor, for the treatment of uveitic macular edema associated with non-infectious uveitis. These studies aim to determine the effect of intravitreal IL-6 inhibition on visual acuity and macular edema reduction.